Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism

Bryan Harris, Dinesh K Singh, Monika Verma, Shawn P Fahl, Michele Rhodes, Shanna R Sprinkle, Minshi Wang, Yong Zhang, Jaqueline Perrigoue, Rachel Kessel, Suraj Peri, Joshua West, Orsi Giricz, Jacqueline Boultwood, Andrea Pellagatti, K H Ramesh, Cristina Montagna, Kith Pradhan, Jeffrey W Tyner, Brian K KennedyMichael Holinstat, Ulrich Steidl, Stephen Sykes, Amit Verma, David L Wiest

Research output: Working paperPreprint

Abstract

UNLABELLED: We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from increased expression of the Rpl22 target, ALOX12, an upstream regulator of fatty acid oxidation (FAO). The increased FAO mediated by Rpl22-deficiency also persists in leukemia cells and promotes their survival. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC via non-canonical de-repression of its target, ALOX12, which enhances FAO, a process that may serve as a therapeutic vulnerability of Rpl22 low MDS and AML leukemia cells.

HIGHLIGHTS: RPL22 insufficiency is observed in MDS/AML and is associated with reduced survivalRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesisRpl22-deficiency does not impair global protein synthesis by HSCRpl22 controls leukemia cell survival by non-canonical regulation of lipid oxidation eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through effects on ALOX12 expression, a regulator of fatty acid oxidation.

Original languageEnglish
DOIs
StatePublished - May 1 2023

Publication series

NamebioRxiv

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    Patterson, MLAS, CMAR, RLATg, ILAM, K. S. (Director), Pimble, AS, A. T. (Manager) & Tuohy VMD, K. (Staff)

    Equipment/facility: Facility

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